Self-Cleaving Protein C Polypeptide for Prolonged Anticoagulant Activity

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Solution Overview

Problem

Current treatments for congenital protein C deficiency, such as Anact C, have limitations including a short half-life, need for continuous administration, and risks associated with anticoagulant therapy, which can lead to bleeding or thrombosis complications.

Innovation Solution

A modified protein C polypeptide with a self-cleaving site inserted at the thrombin cleavage site, allowing for spontaneous activation and increased protein C activity, is expressed in cultured cells and mice using viral vectors, thereby generating activated protein C with prolonged activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Anact C (activated protein C preparation) is used to treat neonatal purpura fulminans, then the condition can be treated, but the half-life is extremely short requiring continuous administration

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidhalf-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the protein C molecule by changing amino acid parameters (substituting amino acids at specific positions) to create a variant with prolonged half-life while maintaining treatment effectiveness. This parameter change in the molecular structure resolves the contradiction between short half-life and treatment reliability.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If anticoagulant therapy with warfarin is used during the stable phase, then thrombosis tendency can be controlled, but bleeding tendency develops due to the drug

Engineering Contradiction:

Improvethrombosis controlVSAvoidbleeding risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent creates a protein C variant that inherently provides both thrombosis protection and reduced bleeding risk by modifying the protein's molecular structure. This converts the harmful effect of warfarin-induced bleeding into a beneficial effect where the modified protein C itself provides balanced anticoagulation without excessive bleeding tendency.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Quantity of substance

If plasma is used for production of Anact C, then activated protein C can be obtained, but risk of unknown infections is introduced

Engineering Contradiction:

Improveprotein C availabilityVSAvoidinfection risk

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent creates a recombinant protein C variant using genetic engineering techniques, copying the functional properties of natural protein C while eliminating the need for plasma derivation. This allows production of infection-free protein C through cellular expression systems, resolving the contradiction between protein availability and infection risk.

Inventive Principle:

Principle #26Copying

4Reliability

If wild-type human protein C is used, then biological activity is maintained, but anticoagulant activity is insufficient requiring frequent administration

Engineering Contradiction:

Improvebiological activityVSAvoidanticoagulant activity

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent modifies specific amino acid parameters in the protein C sequence (substitutions at defined positions) to enhance anticoagulant activity while preserving biological function. This parameter optimization resolves the contradiction between maintaining biological activity and increasing anticoagulant potency.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The modified protein C polypeptide achieves increased protein C activity and anticoagulant action in both cell culture supernatants and mouse blood, potentially offering a more stable and effective treatment for congenital protein C deficiency.

Implementation Method 1

a modified protein C polypeptide into which a self-cleaving site has been inserted

Methodology Applied

Scientific EffectSelf-cleaving:

Data Source

PatentUS20250177571A1Sequence of activated protein c

Publication Date: 2025.06.05 JICHI MEDICAL UNIVERSITY

AI summary

The invention provides a polypeptide or a partial polypeptide thereof, containing an amino acid sequence represented by the formula:A1—A2—A3 (I)wherein A1 is an amino acid sequence comprising an amino acid sequence of a light chain of protein C or a homologue thereof, A2 is an amino acid sequence constituting a self-cleaving site, and A3 is an amino acid sequence comprising an amino acid sequence of a heavy chain of protein C or a homologue thereof, wherein a dimeric protein or partial protein thereof consisting of fragments on the N-terminal side and C-terminal side of the cleavage site of A2, has protein C activity. The polypeptide or partial polypeptide thereof makes it possible to 1) produce activated protein C as a recombinant preparation, and 2) link same to effective gene therapy for protein C deficiency.